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The LRIG-family: identification of novel regulators of ErbB signaling with clinical implications in astrocytoma
Umeå University, Faculty of Medicine, Department of Radiation Sciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Astrocytic tumors are the most common malignancies of the central nervous system, accounting for more than 60% of all primary brain tumors. The prognosis for high grade astrocytoma patients is dismal and there is no curative treatment, today. A molecular hallmark of astrocytic tumors is dysregulated receptor tyrosine kinase signaling, especially of the epidermal growth factor receptor (EGFR, ErbB1). The aim of the present thesis was to identify endogenous human proteins that downregulate the function of the ErbB1 receptor. We identified a human gene family, the leucine-rich repeats and immunoglobulin-like domains family (LRIG), consisting of LRIG1, LRIG2 and LRIG3, which might fulfill this criterion.

Two candidates were identified, LRIG1 and LRIG2, which genes were localized to regions frequently deleted in human cancers, chromosome bands 3p14 and 1p13, respectively. LRIG1 and LRIG2 mRNA were expressed in all tissues analyzed, with high expression in brain and other organs. The LRIG mRNA were predicted to encode integral membrane proteins. Antibodies against LRIG1 and LRIG2 were developed and the protein expression was analyzed. LRIG1 was found to have an apparent molecular weight of 143 kDa and was expressed in most tissues with high expression in glandular tissues of the breast and prostate, and the peptic cells of the stomach. LRIG2 was slightly smaller and had an apparent molecular weight of 132 kDa. The LRIG proteins were localized to the cell surface and to perinuclear structures, where LRIG1 co-localized with the trans-Golgi network and early endosomes.

LRIG1 was found to restrict growth factor signaling by enhancing receptor ubiquitylation and degradation. We showed that LRIG1 interacted with all four members of the ErbB family and induced their downregulation. The interaction with ErbB1 involved both the LRR-domains and the Ig-like domains of LRIG1. LRIG1 enhanced receptor degradation by recruiting the E3 ubiquitin ligase c-Cbl to the LRIG1-ErbB1 complex.

LRIG1, LRIG2, and LRIG3 were expressed in glioma cell lines and tumor tissues. The LRIG expression was analyzed in 404 astrocytic tumor samples. We found that perinuclear LRIG protein expression correlated with increased survival of patients with astrocytic tumors. Especially perinuclear LRIG3 showed strong correlations with patient survival and tumor cell proliferation index.

In summary, this thesis contains the discovery and characterization of human LRIG1 and LRIG2. LRIG1 was found to interact with ErbB receptors and downregulate their function. In a clinical material, expression of LRIG proteins correlated with survival in patients with astrocytic tumors.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2006. , 41 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1027
Keyword [en]
astrocytic tumors, EGFR, ErbB, glioblastoma multiforme, LRIG, negative regulation.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-783ISBN: 91-7264-074-X (print)OAI: oai:DiVA.org:umu-783DiVA: diva2:144516
Public defence
2006-05-24, 244 Lionssalen, By 7, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-05-03 Created: 2006-05-03 Last updated: 2012-04-03Bibliographically approved
List of papers
1. Cloning, characterization and expression of human LIG1
Open this publication in new window or tab >>Cloning, characterization and expression of human LIG1
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2001 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 284, no 5, 1155-1161 p.Article in journal (Refereed) Published
Abstract [en]

Growth factor receptors are frequently amplified and over-expressed in various human cancers. Recently, a Drosophila cell surface protein, Kekkon-1, was found to participate in an epidermal growth factor (EGF) driven negative feedback loop. Kekkon-1 is induced by EGF, binds to the EGF-receptor, and inhibits receptor-mediated signaling. Here, we have searched for human genes with homologies to Kekkon-1 and identified human LIG1. The gene is the human homologue of mouse Lig-1 and is located on chromosome band 3p14, a region frequently deleted in various human cancers. It is predicted to encode a transmembrane cell-surface protein with extracellular leucine-rich repeats and immunoglobulin-like domains. LIG1 mRNA was detected in all tissues analyzed. The highest and lowest relative expression levels were found in brain and spleen, respectively, and differed by more than 200-fold. Taken together, our data are compatible with a role for LIG1 as a growth and tumor suppressor in human tissues.

Keyword
LIG-1, 3p14, EGF, cancer, tumor suppressor, FISH, real-time PCR
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-5120 (URN)10.1006/bbrc.2001.5092 (DOI)11414704 (PubMedID)
Available from: 2006-05-03 Created: 2006-05-03 Last updated: 2017-12-14Bibliographically approved
2. LRIG1 protein in human cells and tissues
Open this publication in new window or tab >>LRIG1 protein in human cells and tissues
2003 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 312, no 1, 65-71 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-5121 (URN)10.1007/s00441-003-0697-1 (DOI)12684867 (PubMedID)
Available from: 2006-05-03 Created: 2006-05-03 Last updated: 2017-12-14Bibliographically approved
3. Characterization and tissue-specific expression of human LRIG2
Open this publication in new window or tab >>Characterization and tissue-specific expression of human LRIG2
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2004 (English)In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 332, 35-43 p.Article in journal (Refereed) Published
Abstract [en]

We have recently identified and cloned the human LRIG1 gene (formerly LIG1). LRIG1 is a predicted integral membrane protein with a domain organization reminiscent of the Drosophila epidermal growth factor (EGF)-receptor antagonist Kekkon-1. We have searched for additional members of the human LRIG family and identified LRIG2 (KIAA0806). The LRIG2 gene was localized to chromosome 1p13 and had an open reading frame of 1065 amino acids. The LRIG2 protein was predicted to have the same domain organization as LRIG1 with a signal peptide, an extracellular part containing15 leucine-rich repeats and three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. The LRIG2 amino acid sequence was 47% identical to human LRIG1 and mouse Lrig1 (also known as Lig-1). Northern blotting and RT-PCR revealed LRIG2 transcripts in all tissues analyzed. Quantitative real-time RT-PCR showed the most prominent RNA expression in skin, uterus, ovary, kidney, brain, small intestine, adrenal gland, and stomach. Immunoblotting of COS-7 cell lysates demonstrated that heterologously expressed human LRIG2 had an apparent molecular weight of 132 kDa under reducing gel-running conditions. N-glycosidase F treatment resulted in a reduction of the apparent molecular weight to 107 kDa, showing that LRIG2 was a glycoprotein carrying N-linked oligosaccharides. Cell surface biotinylation experiments and confocal fluorescence laser microscopy demonstrated expression of LRIG2 both at the cell surface and in the cytoplasm. LRIG2 was detected in tissue lysates from stomach, prostate, lung, and fetal brain by immunoblotting. In conclusion, LRIG2 was found to be a glycoprotein which was encoded by a gene on human chromosome 1p13 and its mRNA was present in all tissues analyzed.

Keyword
Leucine-rich repeats and immunoglobulin-like domains, LRIG1, Lig-1
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-15347 (URN)10.1016/j.gene.2004.02.002 (DOI)15145052 (PubMedID)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2017-12-14Bibliographically approved
4. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation
Open this publication in new window or tab >>LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation
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2004 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 23, no 16, 3270-3281 p.Article in journal (Refereed) Published
Keyword
Cancer, growth factor, signal transduction, tyrosine kinase, ubiquitin ligase
Identifiers
urn:nbn:se:umu:diva-15328 (URN)10.1038/sj.emboj.7600342 (DOI)15282549 (PubMedID)
Available from: 2007-02-23 Created: 2007-02-23 Last updated: 2017-12-14Bibliographically approved
5. Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors
Open this publication in new window or tab >>Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors
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2006 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 111, no 3, 238-346 p.Article in journal (Refereed) Published
Abstract [en]

We have previously characterized three human leucine-rich repeats and immunoglobulin-like domains (LRIG) genes and proteins, named LRIG1-3 and proposed that they may act as suppressors of tumor growth. The LRIG1 transmembrane protein antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases. In this study, we evaluated the mRNA expression level of LRIG1-3 in human glioma cell lines and control-matched glioma tissues, characterized the sub-cellular localization of an LRIG3–GFP fusion protein, and analyzed the relationship between sub-cellular localization of LRIG1-3 and clinical parameters in 404 astrocytic tumors by immunohistochemistry. LRIG1-3 mRNA was detected in all human glioma cell lines and matched glioma samples, with large differences in the expression levels. Ectopically expressed LRIG3–GFP localized to perinuclear and cytoplasmic compartments, and to the cell surface of transfected glioma cells. Perinuclear staining of LRIG1-3 was associated with low WHO grade and better survival of the patients. Perinuclear staining of LRIG3 was associated with a lower proliferation index and was in addition to tumor grade, an independent prognostic factor. Furthermore, within the groups of grade III and grade IV tumors, perinuclear staining of LRIG3 significantly correlated with better survival. These results indicate that expression and sub-cellular localization of LRIG1-3 might be of importance in the pathogenesis and prognosis of astrocytic tumors.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-13620 (URN)10.1007/s00401-006-0032-5 (DOI)16532360 (PubMedID)
Available from: 2007-12-06 Created: 2007-12-06 Last updated: 2017-12-14Bibliographically approved

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